Blood Droplet-Based Cancer Diagnosis via Proteolytic Activity Measurement in Cancer Progression

Abstract

Matrix metalloproteinase (MMP) is a key marker and target molecule for cancer diagnosis, as MMP is able to cleave peptide chains resulting in degradation of extracellular matrix (ECM), a necessary step for cancer development. In particular, MMP2 has recently been recognized as an important biomarker for lung cancer. Despite the important role of detecting MMP molecules in cancer diagnosis, it is a daunting task to quantitatively understand a correlation between the status of cancer development and the secretion level of MMP in a blood droplet. Here, we demonstrate a nanoscale cancer diagnosis by nanomechanical quantitation of MMP2 molecules under cancer progression with using a blood droplet of lung cancer patients. Specifically, we measured the frequency dynamics of nanomechanical biosensor functionalized with peptide chains mimicking ECM in response to MMP2 secreted from tumors in lung with different metastasis level. It is shown that the frequency shift of the biosensor, which exhibits the detection sensitivity below 1 nM, enables the quantitation of the secretion level of MMP2 molecules during the progression of cancer cells or tumor growth. More importantly, using a blood droplet of lung cancer patients, nanomechanical biosensor is shown to be capable of depicting the correlation between the secretion level of MMP2 molecules and the level of cancer metastasis, which highlights the cantilever-based MMP2 detection for diagnosis of lung cancer. Our finding will broaden the understanding of cancer development activated by MMP and allow for a fast and point-of-care cancer diagnostics.

Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti‐PD‐1 inhibitor

“…The present study demonstrated that an increase in the plasma level of MMP2 after treatment was significantly associated with the efficacy of anti‐PD‐1 therapy. Since MMP2 has been shown to have a key role in degradation of the extracellular matrix, it is possible that an increase in MMP2 after anti‐PD‐1 therapy might accelerate lymphocyte migration to tumor nests. MMP2 is known to be produced by stromal or tumor cells in the tumor microenvironment, but the changes in the plasma MMP2 level were not positive correlation with those in tumor burden (Supporting Information Fig.…”

Nanotechnology and Matrix Metalloproteinases in Cancer Diagnosis and Treatment

“…On the other hand, a nanomechanical biosensor to measure active MMP-2 has been developed using a cantilever biosensor that detects molecular processes on its surface, producing a change in its deflection fluctuations or resonant frequency ( Choi et al, 2017 )., The biosensor surface was modified with 3-aminopropyltrimethoxysilane and functionalized with PEGylated peptides linked to the sequence GPLGVRGK that contains the cleavage site for MMP-2. The biosensor is installed in a fluid cantilever holder that quantifies MMP-2 in small amounts of fluid samples.…”

A Paper-Based Near-Infrared Optical Biosensor for Quantitative Detection of Protease Activity Using Peptide-Encapsulated SWCNTs

“…Proteases are classified into families based on their catalytic site, i.e., aspartic, cysteine, glutamic, metallo, serine, and threonine proteases [ 1 ]. They are involved in numerous intracellular and extracellular processes and are known to play an important role in cancer [ 2 , 3 , 4 , 5 ], cardiovascular disease [ 6 , 7 ], pancreatitis [ 8 , 9 ], diabetes [ 10 ], viral infections [ 11 ] (including the novel COVID-19 [ 12 ]), and microbial [ 13 , 14 ] infections. Almost 6% of the proteins in the human genome are proteases [ 15 ], and they can be found in biological fluids like saliva [ 16 ], serum [ 17 ], and urine [ 18 , 19 ].…”